Caveolin-1, transforming growth factor-beta receptor internalization, and the pathogenesis of systemic sclerosis.
OBJECTIVE
To review the scientific literature supporting the participation of caveolin-1 in the pathogenesis of tissue fibrosis and the notion that modulation of the caveolin-1 pathway may represent a novel treatment for systemic sclerosis and other fibrotic diseases.


RESULTS
Caveolin-1 plays an important role in the regulation of transforming growth factor-beta (TGF-beta) signaling owing to its participation in TGF-beta receptor internalization. TGF-beta receptor internalized through caveolin-1 lipid rafts undergoes rapid degradation, effectively decreasing TGF-beta signaling. Studies have shown that caveolin-1 knockdown in vitro markedly increased collagen gene expression in normal human lung fibroblasts. Caveolin-1 was reduced in affected systemic sclerosis lungs and skin and in idiopathic pulmonary fibrosis lung tissues and fibroblasts. Increasing caveolin-1 expression markedly improved bleomycin-induced pulmonary fibrosis. Restoration of caveolin bioavailability employing penetratin, a cell-permeable peptide carrier for a bioactive caveolin-1 fragment, abrogated TGF-beta activation of cultured human dermal fibroblasts. Systemic administration of penetratin-caveolin-1 peptide to mice with bleomycin-induced lung fibrosis reduced fibrosis.


CONCLUSIONS
Caveolin-1 plays an important role in the regulation of TGF-beta signaling and participates in the pathogenesis of systemic sclerosis and idiopathic pulmonary fibrosis. Restoration of caveolin function employing active caveolin-1 fragments coupled to cell-permeable carrier peptides may represent a novel approach for their treatment.
Del Galdo
Francesco
F
Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107-5541, USA.
Lisanti
Michael P
MP
Jimenez
Sergio A
SA
D000818:Animals; D021941:Caveolae / Q000378:metabolism; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000150:complications / Q000209:etiology* / Q000378:metabolism / Q000628:therapy; D015398:Signal Transduction
C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D018125:Receptors, Transforming Growth Factor beta